July 13, 2013

Animal-Human Transplants Work For Diabetes Treatment

Northwestern Medicine researchers have completed the first step toward animal-human transplants of insulin-producing cells for people with type-1 diabetes by successfully transplanting islets from one species to another. Islets are the cells that produce insulin. The findings of this study, published online in the journal Diabetes, show the islets survived without immunosuppressive drugs.

The research team has developed a new method that prevented the host body from rejecting the transplanted islets, which has been a huge problem in xenotransplantation - transplants between species.

"This is the first time that an interspecies transplant of islet cells has been achieved for an indefinite period of time without the use of immunosuppressive drugs," said Stephen Miller, the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. "It's a big step forward."

"Our ultimate goal is to be able to transplant pig islets into humans, but we have to take baby steps," said Xunrong Luo, MD, associate professor of nephrology at Northwestern University Feinberg School of Medicine and medical director of the Human Islet Cell Transplantation Program at Northwestern Memorial Hospital. "Pig islets produce insulin that controls blood sugar in humans."

Type-1 diabetes is a hard-to-control disease in which the patient's body does not produce insulin. A transplant of insulin-producing islets from a deceased donor is one important way to control this chronic disease, however there is a severe shortage of islet cells from deceased donors, meaning many on the waiting list don't receive the transplant or suffer damage to their heart, nerves, eyes and kidneys while they wait.

Being able to use islets from another species would provide wider access to transplants for humans, solving a great deal of the problem. The approach has seemed insurmountable until now because of concerns about controlling rejection of transplants from a different species.

The team of scientists at Northwestern persuaded the immune systems of mice to recognize rat islets as their own without rejecting them. The most notable aspect of the method is that it does not require long-term use of drugs to suppress the immune system, as these drugs have serious side effects. The transplanted rat islets lived and produced insulin in the mice for at least 300 days, which is as long as the scientists followed the mice.

Luo said although the barrier from rats to mice is probably lower than that from pigs to humans, the results showed interspecies islet transplants are possible, and more importantly, possible without immunosuppressive drugs.

Rat splenocytes, a type of white blood cell located in the spleen, were removed by the scientists and treated with a chemical that caused their deaths. The dead splenocytes were injected into the mice, where they entered the spleen and liver and were mopped up by scavenger cells. The splenocytes were processed by the scavenger cells, which then presented fragments of them on their own cell surface. This triggered a reaction that told the T-cells to accept the subsequently transplanted islets and not attack them.

Rejection was still a threat, however. Scientists realize that a unique challenge of an interspecies transplant is controlling the B-cells, which are immune cells that produce a majority of antibodies. When the team first attempted to transplant rat islets into mice, the mouse immune system started producing antibodies against the rat cells, causing rejection.

The team realized they needed to kill off the B-cells at the same time they injected the donor islets into the mice. The mice were given B-cell-depleting antibodies, which are already used in a clinical setting in human transplants. The B-cells naturally returned after the transplant, but they no longer attacked the rat islets.

"With this method, 100 percent of the islets survived indefinitely," Luo said. "Now we're trying to figure out why the B-cells are different when they come back."